PRODUCTION AND EVALUATION OF MONOCLONAL ANTIBODIES FOR POTENTIAL USE FOR BORON NEUTRON CAPTURE THERAPY (B16 MELANOMA, MURINE MAMMARY TUMOR, PRENEOPLASTIC LESION, RADIO BIOLOGY, TUMOR HETEROGENEITY).

摘要

The purpose of the present study was to develop monoclonal antibodies (MoAbs) directed against murine tumor associated antigens for targeting boron-10 to tumors. When irradiated by thermal neutrons, boron-10 yields alpha particles that travel a distance of about one cell diameter thus localizing the destruction to the immediate vicinity. Two panels of monoclonal antibodies directed against B16 melanoma and murine mammary tumors have been produced. One MoAb, designated as AMT8, bound to the surface of mammary tumors and their preneoplastic (HAN) lesions, but not to normal mammary tissues. AMT8 was non-reactive with murine mammary tumor virus, and estrogen, progesterone and transferrin receptors. Six MOAbs directed against murine melanomas bound to uncloned B16 cells and to F1, F10, F10('FLR), and BL6 sublines, but showed no reactivity with normal cells. None of these MOAbs bound to murine leukemia virus, gp70, melanin, or transferrin receptors. One antimelanoma MoAB, designated as IB16-6, was selected as a likely candidate for targeting boron to tumors because it was specific to melanomas, bound to greater than 90% of B16 cells, and did not induce modulation of the tumor antigen. To determine the sensitivity of the tumor target, a large comparative study of the effects of different types of radiation on B16 melanoma has been conducted. The relative effectiveness of the types of radiation in this study could be listed in increasing order of magnitude as follows: thermal neutrons < gamma radiation = gamma radiation + boron-10 < X-radiation < fast neutrons < thermal neutrons + boron-10. The D(,0), D(,q), and n for the various forms of radiation were as follows: 150 KeV X-rays-1.4 - 3.0 Gy, 0.6-2.7 Gy, 1-4; 0.622 gamma radiation - 3.4-4.5 Gy, 1.2-3.0 Gy, 1-2; 43 MeV fast neutrons - 1.0 Gy, 0.9-2.0 Gy, 2-6; thermal neutrons - 3.4-6.6, 30-49, 28-4.7 x 10('6). A definite boron-neutron capture effect was seen with drug doses as low as 0.05 mM Na(,2)B(,12)H(,11)SH (11.1 ug/ml Na(,2)B(,12)H(,11)SH or 6.02 ug/ml boron-10). Investigation of linking boron-10 to MoAB is currently underway. However, these studies have demonstrated boron neutron capture therapy may be feasible using existing facilities.